US3040068A - Process for the preparation of n-alkyl-17-amino-1, 3, 5(10)-estratrien-3-ols - Google Patents
Process for the preparation of n-alkyl-17-amino-1, 3, 5(10)-estratrien-3-ols Download PDFInfo
- Publication number
- US3040068A US3040068A US853462A US85346259A US3040068A US 3040068 A US3040068 A US 3040068A US 853462 A US853462 A US 853462A US 85346259 A US85346259 A US 85346259A US 3040068 A US3040068 A US 3040068A
- Authority
- US
- United States
- Prior art keywords
- estratrien
- lower alkyl
- ethanol
- preparation
- group
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
- C07J41/0005—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring the nitrogen atom being directly linked to the cyclopenta(a)hydro phenanthrene skeleton
Definitions
- the present invention relates to new N-alkyl-l7-aminol,3,5(10)-estratrien-3-ol, and its derivatives which are represented by the following structural formula and to a process for the preparation thereof.
- R is selected from hydrogen, acyl group, such as acetyl and propionyl, and a lower alkyl group such as methyl and ethyl. Meanwhile, R is a lower alkyl group such as methyl and ethyl.
- Concrete compounds are l7-methylamino-l,3,5(10) estratrien-3-ol and l7-ethylamino-1,3,5 10) -estratrien-3- 01, their 3-acetates, 3-propionates, B-methyl ethers and 3- ethyl et-hers. These compounds have not been reported in the literature and have not only antibiotic action against coli bacillus and tubercle bacillus but also excellent trichogeneous action. Compounds as exemplified by the foregoing formula may be produced in the following way.
- the Schiif bases of steroids can be prepared, for instance, by passing methylarm'ne into the anhydrous ethanolic solution of a ketone such as pregnenolone or by adding the saturated amine solution in an organic solvent such as ethanol, allowing the mixture to stand in a dark and cold place for 3 to 4 days.
- the resulted Schiff bases are reduced to produce the corresponding amines.
- the necessity of storing the mixture in a dark and cold place in the latter process is to prevent side reactions such as resinification.
- This invention does not possess such a defect and is a process which gives the said amines easily, safely, in a short period and with a high yield.
- the method of treatment for the preparation of the Schifi base is selected according to the nature of the starting amine.
- Amines which are either gas at the room temperature or are low-boiling, such as methylamine and ethylamine, are placed under pressure with the steroid in order to dissolve the steroid in the liquified amine.
- the amount of the amine may be in excess and preferably 10 times of the steroid by volume. Since it is advisable to maintain the reaction mixture homogeneous, the use of this amount of the amine and that of an autoclave or a pressure bottle are necessary. If the steroid is not completely soluble in the amine, the organic solvents, such as methanol, ethanol, benzene and ethyl ether, which do not interfere with the reactions, may be used.
- Sodium sulfate and quaternary ammonium salts may also be added as catalysts.
- the reaction proceeds smoothly at the room temperature but heating may be applied if necessary. Inside pressure of the autoclave is determined by the vapor pressure of the amine but the process is operative up to 20 atm. when heated. The unreacted amine may be easily and completely recovered after the reaction.
- the high-boiling amine such as propylamine and butylamine, does not necessarily require an autoclave or a pressure bottle.
- the process can be carried out in a suitable solvent such as benzene either at the room temperature or by heating.
- the process may be also performed by adding amine salt such as hydrochloride and sulfate and basic materials such as sodium carbonate and potassium carbonate to a solution of the steroid in an organic solvent such as benzene either at the room temperature or at higher temperature.
- Amines used in the process of the present invention may be primary but the secondary amines are not suitable.
- sodium boron hydride in ethanol is preferable but lithium aluminum hydride in anhydrous ether and metallic sodium in alcohol may be satisfactorily used, giving N'alkyl-l7- amino-1,3,5(10)-estratrien-3-ol or its ethers.
- the first process The preparation of Schiif bases from steroids.
- Example 1 A solution of 1 gr. of estrone, small amount of calcium chloride and 15 cc. methylamine in 15 cc. benzene is heated at 70 C. for 6 hours in a pressure bottle. After the reaction, the unreacted methylamine is recovered by distillation and the residue is treated with 20 cc. of Water. The benzene layer is separated, washed with water and dried with anhydrous sodium sulfate. Removal of the solvent and recrystallization gives 980 mg. 17-methylimino-l,3,5(10)-estratrien-3-ol, needles. It decomposes at 271 C. and has ultraviolet absorption maximum at 281 m, truth a molecular extinction coeflicient of 27 40 in ethanol.
- Example 2 1 gr. of estrone acetate, 15 cc. of ethanol and 15 cc. of methylamine are allowed to react in a pressure bottle at 60 C. for 3 hours. After the reactions, methylamine is recovered and 20 cc. of water is added to the residue. The residue is extracted with benzene. The benzene layer is washed with water, dried with anhydrous sodium sulfate and evaporated. The residue is recrystallized from methanol to give 910 mg. l7-methylimino-1,3,5'(l0)- estratrien-3-ol.
- Example 4 2 gr. of estrone, 2 gr. of anhydrous sodium carbonate, 2 gr. of ethylamine hydrochloride and 30 cc. of benzene are heated for 5 hours in an esterification apparatus. Water is added to the mixture which is extracted with benzene. The benzene layer is treated as mentioned above and evaporated. The residue is recrystallized from methanol to give 1.05 gr. 17-ethylimino-l,3,5(10)-estratrien-3- ol, colorless needles. It decomposes at 235 C. and has an ultraviolet absorption maximum at 280 m l with a molecular extinction coefiicient of 2310 in ethanol.
- the second process The preparation of N-alkyl-17- amino-1,3,5()-estratrien-3-ol or its alkyl ethers.
- Example 5 C and has an ultraviolet absorption maximum at 281 mg with a molecular extinction coefiicient of 1865 in ethanol.
- Example 6 A solution of 500 mg. of 17-methylimino-1,3,5(l0)- estratn'en-3-ol 3-methyl ether and 1 gr. of sodium boron hydride in anhydrous ethanol is stirred overnight. Acetic acid is added to the solution and ethanol evaporated. The residue is treated With water and filtered. The crystals are recrystallized from ethanol to give 420 mg. 17-
- Example 7 3 gr. of sodium metal is added to a hot solution of 1 gr. of 17-ethylimino-1,3,5(10)-estratrien-3-ol in isopropyl alcohol.
- the solvent is removed in vacuo and the residue is acidified with 2 N hydrochloric acid.
- the crystals are taken up in benzene and the solution is shaken with aqueous ammonia.
- the benzene layer is washed with water, treated at the room temperature and evaporated.
- the residue is recrystallized from ethanol to give 570 mg. 17- ethylamino-l,3,5( lO)-estratrien-3-ol, colorless needles. It melts at 164 C. and has an ultraviolet absorption maximum at 281 mp. with a molecular extinction coeficient of 2470 in ethanol.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
Description
United States Patent 3,040,068 PROCESS FQR THE PREPARATION OF N-ALKYL- 17-AN1INO-1,3,5(10)-ESTRA'IRIE1 -3-OLS Iss Chuman, 2370 Lchome, Araijuku, Octa -kn, Tokyo,
Japan; Masanobu Sawai, 193 Kakinokizaka, Megurokn, Tokyo, Japan; and Yasushi Suzuki, 127 Shirahata Minami-cho, Yokohama, Japan No Drawing. Filed Nov. 17, 1959, 'Ser. No. 853,462 Claims priority, application Japan Nov. 22, 1958 5 Claims. (Cl. 260-4975) The present invention relates to new N-alkyl-l7-aminol,3,5(10)-estratrien-3-ol, and its derivatives which are represented by the following structural formula and to a process for the preparation thereof.
RI l NH In the above formula R is selected from hydrogen, acyl group, such as acetyl and propionyl, and a lower alkyl group such as methyl and ethyl. Meanwhile, R is a lower alkyl group such as methyl and ethyl.
Concrete compounds are l7-methylamino-l,3,5(10) estratrien-3-ol and l7-ethylamino-1,3,5 10) -estratrien-3- 01, their 3-acetates, 3-propionates, B-methyl ethers and 3- ethyl et-hers. These compounds have not been reported in the literature and have not only antibiotic action against coli bacillus and tubercle bacillus but also excellent trichogeneous action. Compounds as exemplified by the foregoing formula may be produced in the following way. The Schiif bases of steroids can be prepared, for instance, by passing methylarm'ne into the anhydrous ethanolic solution of a ketone such as pregnenolone or by adding the saturated amine solution in an organic solvent such as ethanol, allowing the mixture to stand in a dark and cold place for 3 to 4 days. The resulted Schiff bases are reduced to produce the corresponding amines. The necessity of storing the mixture in a dark and cold place in the latter process is to prevent side reactions such as resinification.
This method requires not only a considerable amount of solvent and reagent but gives a poor yield as low as 10% after the long period. Hence the process is generally not practical.
This invention does not possess such a defect and is a process which gives the said amines easily, safely, in a short period and with a high yield.
In the present invention, the following reactions may take place:
H N R estates Patented June 19, 1962 In the above equation R and R represent organic groups as mentioned before.
In the present invention, the method of treatment for the preparation of the Schifi base is selected according to the nature of the starting amine.
Amines which are either gas at the room temperature or are low-boiling, such as methylamine and ethylamine, are placed under pressure with the steroid in order to dissolve the steroid in the liquified amine. The amount of the amine may be in excess and preferably 10 times of the steroid by volume. Since it is advisable to maintain the reaction mixture homogeneous, the use of this amount of the amine and that of an autoclave or a pressure bottle are necessary. If the steroid is not completely soluble in the amine, the organic solvents, such as methanol, ethanol, benzene and ethyl ether, which do not interfere with the reactions, may be used. Sodium sulfate and quaternary ammonium salts may also be added as catalysts. The reaction proceeds smoothly at the room temperature but heating may be applied if necessary. Inside pressure of the autoclave is determined by the vapor pressure of the amine but the process is operative up to 20 atm. when heated. The unreacted amine may be easily and completely recovered after the reaction.
The high-boiling amine, such as propylamine and butylamine, does not necessarily require an autoclave or a pressure bottle. The process can be carried out in a suitable solvent such as benzene either at the room temperature or by heating.
The process may be also performed by adding amine salt such as hydrochloride and sulfate and basic materials such as sodium carbonate and potassium carbonate to a solution of the steroid in an organic solvent such as benzene either at the room temperature or at higher temperature. Amines used in the process of the present invention may be primary but the secondary amines are not suitable. For the reduction of Schiif bases, sodium boron hydride in ethanol is preferable but lithium aluminum hydride in anhydrous ether and metallic sodium in alcohol may be satisfactorily used, giving N'alkyl-l7- amino-1,3,5(10)-estratrien-3-ol or its ethers.
The following specific examples serve to illustrate the present invention.
The first process: The preparation of Schiif bases from steroids.
Example 1 A solution of 1 gr. of estrone, small amount of calcium chloride and 15 cc. methylamine in 15 cc. benzene is heated at 70 C. for 6 hours in a pressure bottle. After the reaction, the unreacted methylamine is recovered by distillation and the residue is treated with 20 cc. of Water. The benzene layer is separated, washed with water and dried with anhydrous sodium sulfate. Removal of the solvent and recrystallization gives 980 mg. 17-methylimino-l,3,5(10)-estratrien-3-ol, needles. It decomposes at 271 C. and has ultraviolet absorption maximum at 281 m, truth a molecular extinction coeflicient of 27 40 in ethanol.
Example 2 1 gr. of estrone acetate, 15 cc. of ethanol and 15 cc. of methylamine are allowed to react in a pressure bottle at 60 C. for 3 hours. After the reactions, methylamine is recovered and 20 cc. of water is added to the residue. The residue is extracted with benzene. The benzene layer is washed with water, dried with anhydrous sodium sulfate and evaporated. The residue is recrystallized from methanol to give 910 mg. l7-methylimino-1,3,5'(l0)- estratrien-3-ol.
Example 3 In an autoclave, 1 gr. of estrone 3-methyl ether is dissolved in 10 cc. liquified methylamine and allowed to stand overnight. Methylamine is distilled off and the residue crystallized from methanol to give 0.9 gr. 17-methylimino-1,3,5(l)-estratrien-3-ol 3-methyl ether, colorless needles. It decomposes above 157 C. and has the following ultraviolet absorption maximum in ethanol: 224 my (e=l1500), 278 mp (e==2490) and 289 m (e=2300).
Example 4 2 gr. of estrone, 2 gr. of anhydrous sodium carbonate, 2 gr. of ethylamine hydrochloride and 30 cc. of benzene are heated for 5 hours in an esterification apparatus. Water is added to the mixture which is extracted with benzene. The benzene layer is treated as mentioned above and evaporated. The residue is recrystallized from methanol to give 1.05 gr. 17-ethylimino-l,3,5(10)-estratrien-3- ol, colorless needles. It decomposes at 235 C. and has an ultraviolet absorption maximum at 280 m l with a molecular extinction coefiicient of 2310 in ethanol.
The second process: The preparation of N-alkyl-17- amino-1,3,5()-estratrien-3-ol or its alkyl ethers.
Example 5 C. and has an ultraviolet absorption maximum at 281 mg with a molecular extinction coefiicient of 1865 in ethanol.
Example 6 A solution of 500 mg. of 17-methylimino-1,3,5(l0)- estratn'en-3-ol 3-methyl ether and 1 gr. of sodium boron hydride in anhydrous ethanol is stirred overnight. Acetic acid is added to the solution and ethanol evaporated. The residue is treated With water and filtered. The crystals are recrystallized from ethanol to give 420 mg. 17-
methyl-amino-1,3,5(l0)-estratrien-3-ol 3-methyl ether, colorless prisms. It melts at 122 C. and has the following ultraviolet absorption maxima in ethanol: 225 my (e=l0700), 278 my (e=2150), 289 IIl/L (e=1680).
Example 7 3 gr. of sodium metal is added to a hot solution of 1 gr. of 17-ethylimino-1,3,5(10)-estratrien-3-ol in isopropyl alcohol. The solvent is removed in vacuo and the residue is acidified with 2 N hydrochloric acid. The crystals are taken up in benzene and the solution is shaken with aqueous ammonia. The benzene layer is washed with water, treated at the room temperature and evaporated. The residue is recrystallized from ethanol to give 570 mg. 17- ethylamino-l,3,5( lO)-estratrien-3-ol, colorless needles. It melts at 164 C. and has an ultraviolet absorption maximum at 281 mp. with a molecular extinction coeficient of 2470 in ethanol.
While particular embodiments of the invention have been described, it will be understood, of course, that the invention is not limited thereto, since many modifications may be made; and it is, therefore, contemplated to cover by the appended claims any such modifications as fall within the true spirit and scope of the invention.
The invention having thus been described, What is claimed and desired to be secured by Letters Patent is:
1. The process of preparation of Schiff base exemplified by the general formula wherein R is selected from the group consisting of hydrogen and lower alkyl radicals and R is a lower alkyl radical, by dissolving 17-keto-1,3,5( 10)-estratrien-3-ol and its derivatives represented by the formula wherein R is selected from the group consisting of hydrogen, acyl radicals, and lower alkyl radicals, in a lower primary amine, R'NH wherein R is a lower alkyl group, and recovering the unreacted amine after the reaction is completed.
2. The process of claim 1 wherein an organic solvent is used as a solvent to dissolve the starting materials.
3. The process for the production of the compounds having the structural formula wherein R is a member selected from the group consisting of hydrogen and lower alkyl radicals and R is a member selected from the group consisting of lower alkyl radicals, which comprises reducing the Schifi? base exemplified by the general formula wherein R is selected from the group consisting of hydrogen and lower alkyl radicals and R is a member selected from the group consisting of lower alkyl radicals by sodium boron hydride in ethanol.
4. The process for the production of the compounds having the structural formula wherein R is a member selected from the group consisting of hydrogen and lower alkyl radicals and R is a member selected from the group consisting of lower alkyl radicals, which comprises reducing the Schiff base exemplified by the general formula wherein R is a member selected from the group consisting of hydrogen and lower alkyl radicals and R is a member selected from the group consisting of lower alkyl radicals by metallic sodium in alcohol.
5. The process of preparation of Schifi base exemplifled by the general formula wherein R is -a member selected from the group consisting of hydrogen and lower alkyl radicals and R is a member selected from the group consisting of lower alkyl radicals, by reacting a solution of 17-keto-1,3,5(10)- estratrien-3-ol and its derivatives represented by the formula References Cited in the file of this patent Lettre et al.: Chem. Abst., vol. 37, 5785 (1943).
Shoppee et al.: J. Chem. Soc. (London), January 1959, pp. 345-56.
Royals: Advanced Organic Chemistry (1954), page 650.
Claims (1)
1. THE PROCESS OF PREPARATION OF SCHIFF BASE EXEMPLIFIED BY THE GENERAL FORMULA
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP3040068X | 1958-11-22 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US3040068A true US3040068A (en) | 1962-06-19 |
Family
ID=17927924
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US853462A Expired - Lifetime US3040068A (en) | 1958-11-22 | 1959-11-17 | Process for the preparation of n-alkyl-17-amino-1, 3, 5(10)-estratrien-3-ols |
Country Status (1)
| Country | Link |
|---|---|
| US (1) | US3040068A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11670487B1 (en) | 2022-01-26 | 2023-06-06 | Advanced Energy Industries, Inc. | Bias supply control and data processing |
-
1959
- 1959-11-17 US US853462A patent/US3040068A/en not_active Expired - Lifetime
Non-Patent Citations (1)
| Title |
|---|
| None * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11670487B1 (en) | 2022-01-26 | 2023-06-06 | Advanced Energy Industries, Inc. | Bias supply control and data processing |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US3106564A (en) | 1-(2-phenoxy-2-phenylethyl) pyrrolidine | |
| US2875199A (en) | Lactones of 17-carboxyalkylated estra-1, 3, 5(10)-triene-3, 17-diols and 3-ethers | |
| US3040068A (en) | Process for the preparation of n-alkyl-17-amino-1, 3, 5(10)-estratrien-3-ols | |
| US3009934A (en) | 2beta-halo-3alpha-hydroxy-5alpha-androstan-17-ones and derivatives thereof | |
| US3102127A (en) | 19-methylene-androstane derivatives | |
| US2918463A (en) | 17-carboxyalkylated 17-hydroxy-19-norandrosten-3-ones | |
| US3184500A (en) | O-(beta-acyloxyethyl)-n, n-dialkylhydroxylamines | |
| US3238194A (en) | Optionally n-substituted 17-oxygenated-2-amino-5alpha-androstan-3-ols | |
| US2991295A (en) | 11beta-hydroxy-17alpha-alkyl estrogens and intermediates in the production thereof | |
| US3118933A (en) | N-(alpha-methyl-2, 4-dichlorophenethyl) hydroxylamine and its salts | |
| US2646434A (en) | Method of preparing delta4-pregnenes | |
| US3516991A (en) | Chemical process | |
| US3187022A (en) | 17beta-amino-17alpha-pregnen-20-one compounds and the production thereof | |
| US3092645A (en) | Esters of 17alpha-alkynylester-5(10)-ene-3beta, 17beta-diols | |
| SU677653A3 (en) | Method of producing 2-benzoyl-3-aminopyridine or salts thereof | |
| IL26986A (en) | 7alpha-methyl-delta4,9-steroids of the estrane and gonane series | |
| US3117143A (en) | Optionally 17-alkylated 17-oxygenated 3, 5-cycloandrostane-6 beta, 19-diols and intermediates therreto | |
| US2907758A (en) | 3, 5-cyclo-18, 20-epoxypregnane derivatives | |
| US3032562A (en) | Process for the recovery of 7-dehydrosterols | |
| US3038912A (en) | 20(bets)-[(monoalkylamino)methyl]pregn-5-en-3beta-ols, esters corresponding and intermediates thereto | |
| US3019236A (en) | 20-amino-12, 18-cyclopregnane derivatives | |
| US3148185A (en) | Process for the preparation of 3-hydroxy-6-keto-5beta, 10alpha-steroids | |
| US2812323A (en) | Des-n-methyl erythromycin | |
| US2788364A (en) | Quaternary ammonium salts of dialkylaminoalkyl fluorene-9-carboxylates and the preparation thereof | |
| US3028381A (en) | 6-methyl steroid derivatives and processes of preparing same |